title: Calcitonin gene-related peptide inhibits Langerhans cell-mediated HIV-1 transmission.
abstract: Upon its mucosal entry, human immunodeficiency virus type 1 (HIV-1) is internalized by Langerhans cells (LCs) in stratified epithelia and transferred locally to T cells. In such epithelia, LCs are in direct contact with peripheral neurons secreting calcitonin gene-related peptide (CGRP). Although CGRP has immunomodulatory effects on LC functions, its potential influence on the interactions between LCs and HIV-1 is unknown. We show that CGRP acts via its receptor expressed by LCs and interferes with multiple steps of LC-mediated HIV-1 transmission. CGRP increases langerin expression, decreases selected integrins, and activates NF-κB, resulting in decreased HIV-1 intracellular content, limited formation of LC-T cell conjugates, and elevated secretion of the CCR5-binding chemokine CCL3/MIP-1α. These mechanisms cooperate to efficiently inhibit HIV-1 transfer from LCs to T cells and T cell infection. In vivo, HIV-1 infection decreases CGRP plasma levels in both vaginally SHIV-challenged macaques and HIV-1-infected individuals. CGRP plasma levels return to baseline after highly active antiretroviral therapy. Our results reveal a novel path by which a peripheral neuropeptide acts at the molecular and cellular levels to limit mucosal HIV-1 transmission and suggest that CGRP receptor agonists might be used therapeutically against HIV-1.
authors.affiliation: Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Cell Biology and Host Pathogen Interactions, Cochin Institute, French National Centre for Scientific Research (CNRS; UMR 8104), 75014 Paris, France.
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Ganor
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Drillet-Dangeard
authors.forename: Lucia
authors.initials: L
authors.lastname: Lopalco
authors.forename: Daniela
authors.initials: D
authors.lastname: Tudor
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tambussi
authors.forename: Nicolas Barry
authors.initials: NB
authors.lastname: Delongchamps
authors.forename: Marc
authors.initials: M
authors.lastname: Zerbib
authors.forename: Morgane
authors.initials: M
authors.lastname: Bomsel
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D054405:Chemokine CCL3 / Q000378:metabolism; D005260:Female; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007801:Langerhans Cells / Q000378:metabolism / Q000821:virology*; D037181:Lectins, C-Type / Q000378:metabolism; D008253:Macaca mulatta / Q000821:virology; D008297:Male; D037241:Mannose-Binding Lectins / Q000378:metabolism; D009092:Mucous Membrane / Q000187:drug effects / Q000821:virology; D015302:Simian Immunodeficiency Virus; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015703:Antigens, CD; C121916:CD207 protein, human; D054405:Chemokine CCL3; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D015740:Calcitonin Gene-Related Peptide